We have proposed that malaria pathogenesis is due to a complex interaction between the hemostasis system, the immune response, and parasite sequestration. The overall goal of this proposal is to identify the mechanisms whereby platelet-CD40 contributes to the activation of the platelets and experimental cerebral malaria (ECM) coagulopathy. Definition of ECM pathogenesis is required to develop adjunctive therapy aimed at protecting CM patients from the host response leading to death, cognitive impairment, and psychoses while the anti-parasite treatment kills P. falciparum. We hypothesize that CD40 is a platelet molecule critical for ECM pathogenesis and functions by contributing to platelet activation, microparticle formation, and hence ECM coagulopathy. Little if any information is known about the molecules on platelets that function in ECM pathogenesis. Using an adoptive transfer model of platelets, our preliminary data indicate that platelet CD40 restores the development of ECM to ECM-resistant CD40-KO mice. Aim 1 is focused on confirming these data and determining whether platelet CD40 restores vascular leak, hemorrhage, and leukocyte adhesion in the brains of CD40-KO;these pathogenic processes are hallmarks of ECM. The mechanisms whereby platelets function in ECM pathogenesis are controversial with most investigators focusing on the late stages of ECM where few platelets are present due to thrombocytopenia. However, we have reported that platelets are activated early (~day 1) during ECM and function early in the activation of the pathogenic host response. Our results also document that thrombocytopenia is not sufficient for the genesis of ECM because several strains of ECM-resistant mice exhibit profound thrombocytopenia similar to controls. Key events in platelet biology leading to the activation of the coagulation system include the increase in surface area, degranulation, release of microparticles, and the change in affinity of key surface receptors. Our data indicate that platelets alter their size and expression of surface markers early during ECM and form platelet microparticles, which likely function in ECM pathogenesis. Our second aim is to determine the role of platelet CD40 in platelet activation and microparticle formation during ECM and how this leads to ECM coagulopathy. Our results represent identification of the first platelet molecule functioning in ECM pathogenesis and allow us to investigate the mechanisms whereby platelets contribute to ECM pathogenesis. Our team is the leading group in ECM pathogenesis with a strong track record in investigating platelet biology and its contributions to ECM. These studies are novel, important and can be performed in the limited 2 year time frame with a low budget, making the proposal suitable for the RO3 grant mechanism. PUBLIC HEALTH RELEVANCE: Malaria is a leading cause of morbidity and mortality due to a single infectious agent but there is little consensus regarding any adjunctive treatment of patients presenting with cerebral malaria;this is because we do not understand pathogenesis. We have reported that platelets and platelet microparticles function in cerebral malaria and we now investigate the role of a specific platelet molecule CD40 in pathogenesis.